Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, irreversible memory loss, disorientation and language impairment. It is the most common cause of dementia in the United States. AD can strike persons as young as 40-50 years of age, but because the presence of the disease is difficult to detect without histopathological examination of brain tissue, the time of onset in living subjects is unknown. The prevalence of AD increases with age, with estimates of the affected population as high as 40% by ages 85-90.
AD is only definitively diagnosed through postmortem examination of brain tissue, when pathologists examine the brain tissue for the presence of abundant senile plaques (SPs) composed of amyloid-β (Aβ) peptide aggregates and neurofibrillary tangles (NFTs) formed by filaments of highly phosphorylated tau proteins. An amyloid deposit is formed by the aggregation of amyloid peptides, followed by the further combination of aggregates and/or amyloid peptides. The fibrillar aggregates of amyloid peptides, Aβ1-40 and Aβ1-42, are major metabolic peptides derived from amyloid precursor protein that are found in senile plaques and cerebrovascular amyloid deposits in AD patients.
Parkinson's Disease (PD), another common neurodegenerative disease, is a progressive disorder characterized by resting tremors, bradykinesia, muscular rigidity, and postural instability. PD affects men and women without distinction, regardless of social, ethnic, economic or geographic backgrounds. PD usually develops after the age of 60, though 15% of those diagnosed are under the age of 50. Family history of PD is an etiological factor for 5-10% of patients diagnosed with the disease, yet only 1% of cases have been shown to be clearly familial. It is estimated that 1.5 million Americans are currently living with Parkinson's Disease.
Dementia with Lewy Bodies (DLB) is a progressive neurodegenerative disorder characterized by symptoms that fluctuate between various degrees of manifestation. Such symptoms include progressive dementia, Parkinsonian movement difficulties, hallucinations, and increased sensitivity to neuroleptic drugs. As with AD, advanced age is considered to be a risk factor for DLB, with average onset typically between the ages of 50-85. 20% of all dementia cases are caused by DLB and over 50% of PD patients develop Parkinson's Disease Dementia (PDD), a type of DLB. DLB may occur alone or in conjunction with other brain abnormalities, including those involved in AD and PD, as mentioned above. Currently, conclusive diagnosis of DLB is made during postmortem autopsy.
PD and DLB share an etiology of dopamine deficiency, which is correlated with the death of dopaminergic neurons in the substantia nigra. Dopamine is a neurotransmitter that allows for smooth, coordinated function of the body's muscles and movement. The cause of dopaminergic neuronal death in PD is unknown, but it is recognized that in DLB, abnormal protein deposits called Lewy body proteins or “Lewy bodies” are instrumental in the death of dopaminergic neurons. Lewy bodies occur mostly in the substantia nigra and locus ceruleus sections of the brain stem and also, to a lesser extent, in the subcortical and cortical regions of the brain. Because of this specific localization in the brain, Lewy bodies also interfere with the production of acetylcholine, causing disruption in perception, thinking and behavior. Lewy bodies are also typically considered to be a type of SP, as Lewy bodies are made up of aggregated α-synuclein protein deposits.
An additional etiology of neurodegeneration can be a mixture of pathologies that involves a component of microvascular, or perfusion, deficits in the brain. Commonly referred to as “mixed dementia”, this type of neurodegeneration often involves both perfusion deficits as well as amyloid plaque pathology. Different meanings have been associated with the term mixed dementia. One definition of mixed dementia encompasses a combination of AD and other pathologies such as hypothyroidism, or vitamin B-12 deficiency. However, mixed dementia is most commonly refers to the coexistence of AD and vascular dementia (VaD). Mixed dementia is clinically important because the combination of AD and VaD may have a greater impact on the brain than either by itself. Mixed dementia is traditionally difficult to diagnose, although symptoms are generally similar to those of AD or VaD or a combination of the two.
Because of the central role of the presence of Aβ plaques in AD and death of dopaminergic neurons in PD and DLB, there has been a wide interest in developing radiolabeled ligands that bind to and allow imaging of such abnormalities. Several radioisotopically-labeled Aβ-aggregate-specific ligands have been reported for the imaging of amyloid plaque in the living subject using positron emission tomography (PET) or single photon emission computed tomography (SPECT). These ligands are mainly targeted to nigrostriatal neurons and D2/D3 receptors in the brain. Examples of such radioisotopically-labeled Aβ-aggregate-specific ligands include [(99m)Tc]TRODAT-1 and [(123)I]IBZM, among many others. In addition, several radiopharmaceuticals have been used for PET or SPECT imaging of regional cerebral perfusion. PET radiopharmaceuticals such as 15O-labeled water (H215O) and 13N-ammonia (13NH3) have been employed for perfusion imaging. SPECT radiopharmaceuticals such as Tc-99m HMPAO and Tc-99m Bicisate are also used as cerebral perfusion agents.
Dual-isotope imaging techniques have been employed in trials including parathyroid-studies to detect the existence of an adenoma on the thyroid and in myocardial imaging studies of perfusion and myocardial tissue viability. Additionally, in the brain, a simultaneous 18F-FDG and 99mTc-HMPAO SPECT imaging technique has been utilized to image selected areas in the neuroanatomy of anxiety and depression such as the hippocampus, basal ganglia and gyri temporales superiores. There have also been studies employing a dual SPECT imaging technique with [99mTc]TRODAT-1 and [123I]IBZM to image nigrostriatal neurons and D2/D3 receptors.